Project 2 focuses on the clinical features associated with chronic traumatic encephalopathy (CTE) and chronic traumatic brain injury (cTBI) pathologies. Currently, CTE only can be diagnosed neuropathologically. Diagnosing CTE in life is critical so that incidence and prevalence can be estimated, the course and prognosis can be understood and therapies can be developed. To an even greater extent than CTE, the clinical correlates of cTBI (defined for the purposes of this project as a chronic cavitary lesion after a moderate to severe TBI) are unknown. The overarching hypothesis of this project is that there are distinct mood, behavior, cognitive, motor and imaging features of CTE and cTBI. We will supplement existing clinical and neuropathological data from each of the eight brain banks with newly collected data to address three specific aims. In Aim 1, we will test the validity and reliability of the traumatic encephalopathy syndrome (TES) clinical criteria. These criteria were previously proposed to diagnose CTE in life, but are also meant to capture other TBI-related neurodegenerative processes. From family members of 225 brain donors across a range of ages and TBI, contact and collision sport and military exposures, clinicians will obtain a semi- structured history. A multi-disciplinary expert consensus panel will assess whether TES criteria are met. We will assess inter-rater reliability and sensitivity, specificity and accuracy using first CTE pathology and then cTBI pathology as the gold-standard. In Aim 2, we will use clinical features to construct predictive models of CTE and cTBI pathology. For 1,500 brain donors from across the brain banks, we will use existing data and collect from family members additional extensive structured clinical data, including a variety of cognitive, mood, behavior and motor symptoms. We will use the clinical features to build predictive models of CTE and cTBI pathology using knowledge guided and pure data-driven (machine learning) methodologies. In Aim 3, we will investigate structural MRI and neuropsychological (NP) correlates of CTE and cTBI pathology. For brain donors from across the brain banks, we will compile previously obtained in-vivo brain MRI scans and NP testing. MRIs will be visually rated for regional atrophy, white matter hyperintensities, cavum septum pellucidum, corpus callosum thinning and microhemorrhages. Using NP reports, we will categorize donors based on cognitive and mood/behavior domains with impairment, including memory, executive function, attention, visuospatial function, language, depression and anxiety. We will test associations between CTE and cTBI pathology, MRI visual ratings and patterns of impairment on NP testing. This project will add comprehensive harmonized clinical information to one of the largest brain donor samples with well- characterized histories of RHI and TBI. Findings from this project will help refine existing clinical diagnostic criteria for CTE and inform future clinical diagnostic criteria for cTBI. Diagnosis in life is pivotal to counsel families about disease course and prognosis and to develop effective therapies.